• Drug Absorption II Continued

  • Membrane Transporters

    • Carrier Mediated Transport

      •  Carrier-mediated transport is distinct from translocation of drugs across the membrane using channels.

    • Facilitated diffusion is drug transport mediated by a carrier and the driving force is the electrochemical gradient associated with the drug.^11,15,16 

      • Facilitated Diffusion in Cell Membrane

        "Facilitated diffusion involves the use of a protein to facilitate the movement of molecules across the membrane. In some cases, molecules pass through channels within the protein. In other cases, the protein changes shape, allowing molecules to pass through." Attribution LadyofHats, Public domain, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Scheme_facilitated_diffusion_in_cell_membrane-en.svg

      • The electrochemical gradient consists of two elements:

        • (1) the difference in drug concentration across the membrane and the electrical gradient (difference in charge across the membrane).

        • (2) Specificity in such transport depends upon the carrier protein.

          • "Diagram of ion concentrations in charge across a semi-permeable cellular membrane"

            "Illustration of the way that differences in ion concentration on opposite sides of the membrane produces a voltage difference." Attribution Gibbs-donnan-en.svg: Biezlderivative work: Looie496, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons https://en.wikipedia.org/wiki/Electrochemical_gradient

      • The carrier protein is typically selective for a set of conformational structures.

        • The importance of the carrier is that absent such a carrier the translocation of the drug across the membrane would be much slower.

        • Drug binding to a carrier molecule induces a change in the complex confirmation which becomes energetically favorable for transporter across the membrane.

    • An example of a facilitated diffusion carrier is the organic cation transporter OCT1 coded by the gene SLC22A1.

      • This transporter, OCT1, not only facilitates transport of a physiological solute, thymine, but also is involved in transport of the drug metformin.

        • Metformin is useful in treating type II diabetes.^11,15,16

      • OCT1 (gene: SLC22A1) is expressed in the liver and exhibits a relatively broad substrate specificity.¹⁷ 

        • OCT1 expression appears to correlate with drug responses.

          • Functionally defective OCT1 appears associated with drug resistance.¹⁷ 

      • Members of the OCT family (e.g. OCT1, OCT2, OCT3) are involved in renal clearance of many drugs.¹⁸  

        • Transport of cations by OCTs is driven primarily by the membrane potential.

        • The OCTs noted above represent isoforms and these isoforms have overlapping substrates.

          • In addition, the tissue localization of these isoforms differ.

            • OCT1 is mainly associated in the sinusoidal or basolateral hepatocyte membranes.

              • Drugs and Endogenous Compounds and their Hepatocyte Transporters¹⁸

                Attribution: Adapted from Figure 5-1 from reference 18 Esroy BA Hoffmaster KA Chapter 5 Drug Transporters in Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy (Golan DE Armstrons EJ Armstong AW, eds) 4e Wolters Kluwer 2017.

            • OCT2 is mainly renal, localized in the kidney proximal tubule.

            • OCT3 is more broadly distributed in tissues including mainly, intestine, kidney, and liver.

              • OCT3 promotes intestinal absorption on one hand and liver and renal secretion of drugs on the other.

        • OCTs are involved in uptake of many drugs including those belonging to the sedative, antidepressant and β-antagonist categories.¹⁸

      
       

References